Revolution Medicines, Inc.

Today, ladies and gentlemen, and welcome to the Revolution Medicine Second Quarter Fiscal Year 2021 Financial Results Conference Call and Webcast. At this time, all participants are on a listen-only mode. Following management's prepared remarks, we will have a question and answer session. To ask a question at that time, please press star followed by the one on your touchtone telephone. Please be advised that today's conference call is being recorded. If anyone has difficulty hearing the conference, please press star zero for operator assistance. I would now like to hand the conference over to Peg Horn, Revolution's Chief Operating Officer, for opening remarks. Peg, you may begin.

Good afternoon, everyone, and thank you all for joining us today. Joining me on today's call are Dr. Mark Goldsmith, Revolution's Chairman and Chief Executive Officer, Dr. Steve Kelsey, the company's President, Research and Development, and Jack Anders, our Senior Vice President of Finance and Principal Accounting Officer. As we begin, I'd like to caution you that our presentation today will contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act regarding the current beliefs of the company with respect to our business. These statements are subject to a number of assumptions, risks, and uncertainties. Actual results may differ materially from these statements, and except as required by law, the company undertakes no obligation to revise or update any forward-looking statements. I encourage you to review the legal disclaimer slide we are presenting today, as well as all of the company's filings with the SEC concerning these other matters. During this presentation, we will be referring to a few slides from our corporate presentation. The entire presentation was posted to our website immediately prior to this call. With that, I will turn the call over to Dr. Mark Goldsmith, Revolutions Chairman and Chief Executive Officer. Mark.

Thank you and good afternoon. Welcome to our Q2 earnings call. This is Revolution Medicine's first earnings call and we look forward to having this opportunity to connect with our investors on a regular basis. After our prepared remarks today, we will host a Q&A session. Treatment for RAS-addicted cancers reached an important milestone in Q2. with the first FDA approval of a targeted medicine for lung cancer carrying the KRAS G12C mutation, Amgen's Lumicras, or Sotiracib. Likewise, R&D at Revolution Medicines continued making excellent progress, reinforcing our belief that the company's innovative and cohesive asset portfolio can drive rational, mechanism-based, and beneficial combination treatments for patients with RAS-addicted cancers. Our ambition is to serve remaining and significant unmet needs for patients with KRAS G12C positive tumors and even larger opportunities to benefit those with cancers driven by other non-G12C RAS variants, as shown on slide four. Today, we will highlight important progress we've made on our exciting tricomplex RAS-on inhibitors that extends the momentum we've described previously. We will also provide an update on several aspects of RMC-4630, an advanced and important asset in our RAS companion inhibitor portfolio. We will report on two combination drug strategies that have been under evaluation in the RMC-4630-02 study. The so-called clamping approach with our SHP2 inhibitor RMC-4630 in combination with the MEK inhibitor, cobimetinib, directed against advanced RAS-addicted cancers lacking a targeted RAS inhibitor. and a second approach with RMC4630 combined with the EGF receptor inhibitor Osimeritinib aiming to enhance clinical benefit in EGF receptor mutant lung cancer. We will also explain our continued commitment to treatment strategies combining a direct RAS inhibitor with RMC4630 and we'll announce an exciting high priority combination study sponsored by Revolution Medicines evaluating RMC4630 in combination with Sotiracib in KRAS G12C-positive lung cancer under a new clinical trial collaboration and supply agreement with Amgen that builds on and is a complement to the CodeBreak 101 trial exploring this combination across multiple cancer types. The RMC4630-03 study is designed to allow us to better define patients who may most benefit from the combination of our SHIP2 inhibitor with the KRAS G12C inhibitor through analysis of cohorts with and without certain commutations. Steve Kelsey, Revolution's President of R&D, will provide more information on the new O3 study and our other clinical programs after I provide an update on our RAS-on inhibitors. For KRAS G12C positive lung cancer and colorectal cancer in particular, we continue to believe there's an opportunity to increase clinical response rates and or durability as suggested by this table on slide five, summarizing some key outcomes reported with first generation KRAS G12C off inhibitors so far that show both the clinical benefit of targeted drug and areas of ongoing opportunities. With these unmet needs in mind, we are pursuing development of several new RAS on inhibitors. A key element of the strategy for our KRAS G12C on inhibitor is consistent with the successful generational paradigm established previously with advanced generation targeted inhibitors for tumors with EGF receptor mutations. In Q1 of 2021, we had introduced the compelling profile of the development candidate RMC6291, our first-in-class potent oral and selective tricomplex inhibitor for KRAS-G12C, as summarized on slide 10. Expanding from earlier examples shown previously, in Q2, we reported additional examples of deeper, more uniform, and or more sustained anti-tumor effects in xenograft KRAS-G12C cancer models compared to a first-generation RAS-OF inhibitor. These experiments are part of a growing body of evidence that RMC69-1 has best-in-class potential among KRAS-G12C inhibitors. Also in Q2, various newly emergent RAS or RAS pathway mutations were reported in 39% of patients exhibiting resistance to treatment with Atagracib. And the described mutations provide a critical roadmap for treatment approaches to combat these mechanisms of clinical failure. As shown in this table on slide 14, the company has expanded on initial results published in Cancer Discovery by Dr. Ryan Corcoran's team at the Massachusetts General Hospital and Harvard Medical School by demonstrating that RMC6291 is active against all second site resistance mutations reported thus far from patients treated with adagracib. As many of these mutations also confer resistance to sotiracib and other KRAS-G12C-Auth inhibitors, the activity of RMC6291 in this setting illustrates a distinguishing property of the molecule that may be useful for preventing or treating emergence of these resistance mutations. RMC-6291 continues on track in its IND-enabling development program toward its expected IND filing in the first half of 2020-22. We also showed additional progress in addressing non-G12C oncogenic RAS variants, which account for approximately 85% of all incident RAS-addicted cancers and for which no targeted treatments are available. Earlier in 2021, we had described the compelling profile of our second development candidate, RMC6236, a first-in-class potent oral and RAS-selective tricomplex inhibitor for multiple variants of RAS, as summarized on slide 17. Expanding from earlier examples of KRAS G12V and KRAS G12D cancer models shown previously, in Q2, we described additional preclinical data in a growing body of evidence that RMC6236 has first-in-class and best-in-class potential for treating KRAS G12V and or KRAS G12D tumors across multiple histotypes. Among the multiple resistance mechanisms, resistance mutations in adagrassive treated patients that were reported in Q2, a notable group of emergent RAS variants was described that are expected to be insensitive to KRAS G12C off inhibitors and to RMC6291. As shown on slide 22, These mutations include new substitutions at KRAS G12 in the upper panel, KRAS G13 in the lower panel, and NRAS Q61 also in the lower right panel. Importantly, we've now shown in preclinical experiments that RMC6236 is active against all of these clinically observed variants, as well as a broader panel of KRAS G12 mutants that to date haven't been described in patients. Hence, these findings indicate that RMC6236 has important properties that may be useful for preventing or treating emergence of these RAS oncogene switch resistance mutations. In Q2, we also reported information about the potential for additive benefit in combinations of either RMC6291 or RMC6236 with a checkpoint inhibitor. For example, as shown on the left of slide 26, in immunocompetent mice engrafted with the syngeneic Ras mutant tumor, RMC6236 induced a favorable transformation of the tumor immune microenvironment characterized by an increase in infiltrating CD8 T cells and a decrease in immune-suppressive M2 macrophages. As shown on the right, RMC6236 alone was quite active against growth of these syngeneic tumor grafts, including inducing a number of complete responses. and anti-PD-1 antibody alone was active as well, but the two together led to complete responses in all animals. These results are encouraging about the potential clinical benefit of combining our RAS-on inhibitors with PD-1 inhibitors in treating anti-PD-1 sensitive tumors. Like RMC6291, RMC6236 continues on track in IND-enabling development, and we continue making very good progress. on advancing additional mutant selective Ras-on inhibitors. Our corporate goal is to select a third development candidate this year to advance into IMD-enabling development and others subsequently. Today, we'd like to show you some new evidence of our drug discovery capabilities by focusing briefly on two programs we disclosed in late lead optimization, KRAS G13C and KRAS G12D. Shown on the left of slide 29, is a graphical surface representation of the SW1-2 region of the Ras-on protein, which shows that amino acids 12, highlighted in blue, and 13, highlighted in red, lie adjacent to each other in the protein, and both are very close to the Ras-on inhibitor binding site, highlighted in dark pink. Our previous work enabled RMC6291 to selectively engage the oncogenic cysteine at position 12 in the mutant KRAS-G12C-on protein, as indicated by the upward shift of the KRAS G12C protein band in the cross-linking experiment on the left. We have now been able to engineer new RAS-on inhibitor compounds that covalently engage the specific oncogenic cysteine at position 13 in the mutant KRAS G13C-on protein, as indicated by the upward shift of the KRAS G13C protein in the middle panel. Further, the exquisite molecular control we bring to the design of these remarkable compounds enable selective covalent binding to the cysteine-13 variant by one compound without detectable binding to the cysteine-12 variant, or conversely, selective covalent binding to the cysteine-12 variant by another compound without covalent binding to the cysteine-13 variant, despite the similar positions of the cysteines at positions 12, and 13 in these RAS variants. Thus, the covalent warheads in these compounds are tuned to work only when positioned precisely and optimally with the free-file group of the particular cysteine residue for which they are designed, a degree of on-target selectivity that is very encouraging. We also report today that we have extended covalent chemistry beyond cysteines to the oncogenic aspartic acid in the KRAS G12D on variant, an exciting innovation and major achievement. Shown on the right of slide 29 is a representative compound that binds and cross-links to the KRAS G12D on variant, as indicated by the upward shift of the KRAS G12D protein. Important evidence of the selectivity of this engagement is the absence of significant cross-linking to its close cousin, the KRAS G13D variant, despite the close proximity of aspartate 12 and aspartame 13 to one another. We're very proud of both of these quite differentiated chemical series that enable potent and highly mutant-selective inhibition of oncogenic RAS signaling. Indeed, as shown here, each of these compounds shows impressive tumor cell growth inhibition in the corresponding genetic context, as anticipated by the specific cross-linking pattern shown above. These laboratory-based feeds offer further insight into the groundbreaking drug design and execution capabilities deployed as we continue expanding our portfolio of RAS on inhibitor assets, and we look forward to providing further updates as these programs reach further milestones. We'd also like to provide an update on the good progress within our RAS companion inhibitor pipeline. Previously, we identified combinations with RAS inhibitors as a core strategic element of our SHIP2 inhibitor program, and we remain optimistic about this strategy. To illustrate this concept, we recently shared data on this example of a drug-resistant KRAS G12C colorectal tumor xenograft in slide 32. In contrast to another colorectal cancer model we showed previously that is highly sensitive to single-agent RMC6291, This particular colorectal cancer model exhibits only a modest growth inhibition response to RMC6291 monotherapy in the blue line, which we believe relates to the role of wild type or normal RAS proteins in supporting growth of these tumors. Notably, combining our shift to inhibitor RMC4550, a tool compound we often use for preclinical research, with RMC6291 induced deep and sustained regressions in the tumor xenografts as shown on slide 32. Hence, while RMC6291 itself has a superior preclinical profile to first generation KRAS G12C inhibitors as measured in a variety of models we've shown previously, additional anti-tumor impact can be obtained by the additive contribution of our SHIP2 inhibitor. We believe that combining such agents in the clinic will prove to be a compelling therapeutic strategy And now I'll turn things over to Dr. Steve Kelsey, our president of R&D, to bring you up to date on these efforts. Thank you, Mark.